Molecular signal networks and regulating mechanisms of the unfolded protein response

Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein （BiP） interacts with the three sensors （protein kinase RNA-like ER kinase （PERK）, activating transcription factor 6 （ATF6）, and inositol-requiring enzyme la （IREla）） Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor （VEGF）-VEGF receptor （VEGFR）-phospholipase C-~ （PLCy）-mammalian target of rapamycin complex 1 （mTORC1） pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase （AKT）. A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species （ROS）, Ca2＋ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase （JNK）, signal transducer and activator of transcription 3 （STAT3）, and P38, when cellular damage exceeds the capacity of this adaptive response.

PM2.5 Exposure Elicits Oxidative Stress Responses and Mitochondrial Apoptosis Pathway Activation in HaCaT Keratinocytes

Background：PM2.5 （aerodynamic diameter ≤ 2.5 μtm） is a dominant and ubiquitous air pollutant that has become a global concern as PM2.5 exposure has been linked to many adverse health effects including cardiovascular and pulmonary diseases.Emerging evidence supports a correlation between increased air PM2.5 levels and skin disorders although reports on the underlying pathophysiological mechanisms are limited.Oxidative stress is the most common mechanism of PM2.5-induced adverse health effects.This study aimed to investigate PM2.5-induced oxidative damage and apoptosis in immortalized human keratinocyte （HaCaT） cells.Methods：HaCaT cells were exposed to 0,25,50,100,or 200 μtg/ml PM2.5 for 24 h.Reactive oxygen species （ROS） generation,lipid peroxidation products,antioxidant activity,DNA damage,apoptotic protein expression,and cell apoptosis were measured.Results：PM2.5 exposure （0-200 μtg/ml） for 24 h resulted in increased ROS levels （arbitrary unit：201.00 ± 19.28,264.50 ± 17.91,305.05 ± 19.57,427.95 ＋ 18.32,and 436.70 ± 17.77） and malondialdehyde production （0.54 ± 0.05 nmol/mg prot,0.61 ± 0.06 nmol/mg prot,0.68 ± 0.05 nmol/mg prot,0.70 ± 0.05 nmol/mg prot,and 0.76 ± 0.05 nmol/mg prot）,diminished superoxide dismutase activity （6.47 ± 0.28 NU/mg prot,5.97 ± 0.30 NU/mg prot,5.15 ± 0.42 NU/mg prot,4.08 ± 0.20 NU/mg prot,and 3.76 ± 0.37 NU/mg prot）,and increased DNA damage and apoptosis in a dose-dependent manner in HaCaT cells.Moreover,cytochrome-c,caspase-3,and caspase-9 expression also increased proportionately with PM2.5 dosing.Conclusion：PM2.5 might elicit oxidative stress and mitochondria-dependent apoptosis that likely manifests as skin irritation and damage.